Mycobacteroides abscessus (formerly known as Mycobacterium abscessus) is a rapidly growing nontuberculous mycobacterium that causes a spectrum of opportunistic infections in humans. In the setting of structural lung conditions such as cystic fibrosis, bronchiectasis and COPD, M. abscessus can cause chronic pulmonary disease. In these settings, M. abscessus infections are often incurable and associated with rapid lung function decline. A growing number of clinical isolates of M. abscessus are resistant to most antibiotics, therefore, new treatment options that are effective against these drug-resistant strains are desperately needed. ?-lactams are the most widely used class of antibiotics globally to treat bacterial infections in humans and have a demonstrated record of safety and tolerability. Among ?-lactams, imipenem and cefoxitin are commonly considered for treating M. abscessus infections. However, today, only a single ?-lactam is used at a time to treat Mab infections. We have completed proof-of-concept studies demonstrating that certain combinations of ?-lactams, each at less than half the dose for single ?-lactams, exhibit synergy in bactericidal activity in vitro and in a mouse model of pulmonary M. abscessus infection. Some of these combinations are comprised of agents that are orally bioavailable. In this proposal, we will identify dual ?-lactam combinations that exhibit synergy in vivo against M. abscessus disease and can be administered orally to achieve stable cure. Subsequently, we identify dual ?-lactams with highest efficacy against a wide variety of M. abscessus strains as there is significant genotypic and phenotypic heterogeneity among M. abscessus stains that cause disease in humans.